Sex differences in drug effects is an area of emerging importance for understanding the neurological bases, etiology, epidemiology, toxicity, prevention and treatment of drug use. There is now solid evidence of gender differences in the serotonin neurotransmitter system that may account for differences in rates of depression and anxiety in men and women and therapeutic responses to SSRIs. Of even greater relevance to the proposed study, gender differences have been confirmed in the dynamics of tobacco smoking and cessation in humans. These differences have been attributed to acute and chronic effects of ovarian steroid hormones on nicotinic receptors, although findings have not been conclusive. Using positron emission technology (PET), we recently have reported robust sex differences in dopamine release (DAR) to amphetamine administration in healthy, age-matched men and women;this is the first demonstration of gender-based DAR differences in human subjects. This research has high significance from both a basic science and clinical intervention perspective. Using PET, the proposed study will examine possible mechanisms for gender-based differences in DAR following amphetamine administration in healthy, age-matched men and women. Female subjects will be scanned during both the luteal and follicular phases of their menstrual cycle. Subjects will complete measures of subjective effects of amphetamine. In addition, we will obtain a sex hormone/neurosteroid profile on male and female subjects and determine the relationship to DAR. If our hypotheses of the roles of sex hormones/neurosteroids in DAR are supported, these findings will be important in understanding the etiology, epidemiology, neurotoxicity, prevention and treatment of stimulant use disorders. Further, the scientific and clinical importance of the results extends beyond addiction to include other disorders involving dopamine in the striatum, including schizophrenia, Parkinson's disease, Huntington's disease and obsessive-compulsive disorder. PUBLIC HEALTH RELEVANCE: Our laboratory has recently found that healthy, young adult men release more dopamine, a brain chemical that influences the rewarding and euphoric effects of stimulant drugs, and report greater "high" and "drug liking" following amphetamine administration compared with age-matched women. The proposed research will study these sex differences, whether the effects of amphetamine change in women during the menstrual cycle, and the role of sex hormones (estrogen, progesterone and testosterone) in modifying drug effects on dopamine. Findings will have considerable public health significance in furthering our understanding of normal sex differences in brain function and hormonal mechanisms for these effects, thus paving the way to better understand these factors in substance abuse and other neuropsychiatric disorders.